PROJECT SUMMARY Chronic kidney disease has become a worldwide epidemic with approximately 26 million people being affected in the United States alone. The primary cause of death in patients with chronic kidney disease (CKD)/ end stage renal disease (ESRD) is from uremic cardiomyopathy and medial vascular calcification resulting in cardiovascular death (CVD). The etiology of CVD in CKD/ESRD is multifactorial, and despite advances made in treating the associated co-morbidities, the survival of patients with CKD/ESRD has not significantly improved. Fibroblast growth factor 23 (FGF23), a phosphaturic hormone secreted by the bone, is elevated early in CKD to maintain normophosphatemia, and, continues to increase with progression of CKD to ESRD to supraphysiological levels. Epidemiological studies have associated FGF23 with increased cardiovascular mortality/morbidity in CKD/ESRD. However, there is conflicting data regarding the direct effects of FGF23 on the heart and the vasculature using animal models and human observational studies. Thus, the biology of FGF23 is poorly understood and there is a need to determine the effects of FGF23 on the cardiovascular system in kidney disease. The applicant's laboratory has developed an innovative mouse model with a compound deletion of fibroblast growth factor receptors (Fgfrs) in the kidney: Kidney Conditional Fgfr1 and Fgfr4 (KCFgfr1-/-/Fgfr4-/- mice) which results in chronic elevation of FGF23 levels without hypophosphatemia due to renal resistance to the phosphaturic actions of FGF23. The applicant's long term goal is to identify the role of FGF23 in health and kidney disease especially in regards to development/progression of CKD, renal fibrosis, inflammation, bone mineralization, and neurocognitive functions. Using the above described mouse model, the overall objective for this proposal is to identify the direct effects of FGF23 on the cardiovascular system in kidney disease. Our preliminary data indicates that there is increased cardiac mass with chronic exposure to FGF23 together with hyperphosphatemia at 6 months of age and there is increased aortic calcification in 12-18 month old mice. We will determine the additional factors that FGF23 requires to cause increased cardiac mass as KCFgfr1-/-/Fgfr4-/- mice have modest hyperphosphatemia, as seen in kidney disease. We will use different dietary regimens to tease out which additional factors are required for FGF23 to have the adverse effects on the heart: hyperphosphatemia, uremic toxins or a combination of both. With this research proposal, we will also study the signaling pathways responsible for conversion of vascular smooth muscle cells into a chondrocyte-like cells promoting vascular calcification. We aim to identify the Fgfrs responsible for promoting vascular calcification in addition to the signaling pathways. The results from this proposal will offer avenues for new therapeutic targets to mitigate the effects of FGF23 on the cardiovascular system which will have a positive impact on the cardiovascular mortality/morbidity of patients with CKD/ESRD.